Glucocorticoids Flashcards
1
Q
Which response does the HPA axis mediate?
A
stress response
2
Q
Which structures does the HPA axis involve?
A
hypothalamus, anterior pituitary gland, adrenal gland
3
Q
What is the stimulus for HPA axis?
A
physical, psychological, environmental stressors
4
Q
Provide an overview of the HPA axis using the hormones involved.
A
stressor –> CRH –> POMC –> ACTH
5
Q
Which hormone potentiates the effects of CRH?
A
vasopressin (AVP)
6
Q
What is the action of ACTH on the adrenal cortex?
A
regulate production of steroid hormones
7
Q
main physiological glucocorticoid
A
cortisol
8
Q
main physiological mineralocorticoid
A
aldosterone
9
Q
Which physiological steroid hormone is produced in the zona fasciculata? Which enzymes are involved?
A
- cortisol
- 17-alpha-hydroxylase, 21-beta-hydroxylase, 11-beta-hydroxylase
10
Q
Which physiological steroid hormone is produced in the zona glomerulosa? Which enzymes are involved?
A
- aldosterone
- 21-beta-hydroxylase, 11-beta-hydroxylase
11
Q
Which physiological steroid hormone is produced in the zona reticularis? Which enzymes are involved?
A
- androstenedione
- 17-alpha-hydroxylase
12
Q
which layer of the adrenal cortex is the only layer that remains functional in the absence of pituitary function?
A
zona glomerulosa
13
Q
primary stress hormone
A
cortisol
14
Q
What are 3 modes of physiological regulation of the HPA axis?
A
- diurnal rhythm in basal steroidogenesis (i.e. rhythmic regulation)
- negative feedback regulation by adrenal steroids
- changes in steroidogenesis in response to stress
15
Q
Describe the rhythmic regulation of the HPA axis.
A
- cortisol secreted in pulsatile, ultraradian rhythm
- also circadian rhythm in females along the estrous cycle
16
Q
Describe the normal circadian rhythm of the HPA axis.
A
- 1) circadian signals from SCN clock genes propagate to hypothalamic nuclei
- 2) light-dark signals to SCN influence HPA –> cortisol production
- 3) GC peak at 8 AM = start of active cycle
- 4) nadir levels during sleeping = inactive phase
- 5) adrenal glands receive sympathetic autonomic innervation –> reduced responsiveness to ACTH during inactive phase
17
Q
Where does GC negative feedback occur in the HPA axis? Where do endogenous GCs induce neg feedback? exogenous?
A
- hypothalamus = endogenous target
- pituitary = exogenous target
18
Q
How do GCs inhibit CRH secretion in negative feedback regulation of the HPA axis?
A
direct effects on hypothalamic CRH neurons
19
Q
How do GCs inhibit ACTH secretion in negative feedback regulation of the HPA axis?
A
- rapid response: inhibit response of corticotrophs to CRH via GR
- delayed response: suppress POMC expression via GR
20
Q
primary target for negative feedback when GC levels are elevated?
A
GR
21
Q
Describe the regulation of GC secretion in acute stress response.
A
- stress (fight/flight response) overrides normal negative feedback control mechanisms
- ACTH increase –> cortisol increases as ACTH falls to basal level
- pulsatility maintained
22
Q
Which plasma proteins are GCs bound to, in order to keep them inactive?
A
- 90% CBG
- 10% albumin
23
Q
which enzyme activates bound GCs in the liver?
A
11-beta-HSD1
24
Q
which enzyme inactivates bound GCs in the kidney?
A
11-beta-HSD2
25
What are the 2 GRs and what is the difference between the 2?
- GR-alpha: transactivation/repression
- GR-beta: inhibit GR-alpha signal
26
Describe GC-GR signaling in direct DNA interaction.
- GRalpha DIMER bind to GRE --> direct transactivation
- GRalpha DIMER bind to nGRE --> direct transrepression
27
Describe GC-GR signaling in composite GRE binding.
GRalpha MONOMER binds to GRE --> recruit co-activators / co-repressors (for transactivation / transrepression)
28
Describe GC-GR signaling in tethering.
GRalpha MONOMER interacts with another TF without contacting DNA --> enhance/decrease capacity of TF to bind DNA and recruit co-regulators
29
What are some non-genomic effects of GCs?
- chaperone protein signaling
- protein-protein interaction
30
effects of cortisol in muscle
catabolic (fatty acid oxidation, proteolysis, decrease glucose uptake)
31
effects of cortisol in pancreas
- acute: stimulate insulin secretion and beta-cell growth
- long-term: inhibit insulin synthesis/secretion and induce beta-cell apoptosis
32
effects of cortisol in heart? permissive or direct?
- vasoconstriction and increase BP
- permissive effects on catecholamines and Ang II
33
effects of cortisol in kidneys? permissive or direct?
- decrease vasopressin secretion and effects
- permissive
34
effects of cortisol on the brain?
- sleep
- appetite
- memory
- cognition
- emotion
- excessive cortisol linked to major depressive disorders
35
effects of cortisol in adipocytes?
- increase lipolysis
- increase lipid uptake
- decrease glucose uptake
- overall: INCREASE IN BODY FAT
36
effects of cortisol in liver? permissive or direct?
- increase gluconeogenesis, glycogenolysis, glycogen storage
- leads to insulin resistance
- permissive effects on glucagon and catecholamines
37
What is the main difference between primary and secondary adrenal insufficiency?
- primary: adrenal glands don't make enough GC/MC
- secondary: pituitary doesn't make enough ACTH
38
How does primary adrenal insufficiency lead to increased CRH and ACTH?
GC deficiency leads to loss of negative feedback on the pituitary and hypothalamus
39
most common inherited form of primary adrenal insufficiency? Which enzyme is affected? How does it affect sex hormones?
- congenital adrenal hyperplasia
- 21-beta-hydroxylase
- increased sex hormones
40
What is the name for acquired primary adrenal insufficiency in adults?
Addison's disease
41
what is the mechanism of Addison's disease?
- destruction of adrenal cortex by T-cell mediated AUTOIMMUNE mechanisms
- B cells in local lymph nodes produce AUTOANTIBODIES against 21-beta-hydroxylase
42
Which adrenal insufficiency disease decreases aldosterone?
primary adrenal insufficiency
43
What is another name for secondary adrenal insufficiency?
Cushing's disease
44
what is the most common cause of tertiary adrenal insufficiency?
exogenous administration of GCs
45
which adrenal insufficiency disease is characterized by the following:
- round, red, full face
- buffalo hump
- thin skin
- excess body hair
- central obesity
- interrupted menstrual cycle
cushing's syndrome
46
Which hormone does Cushing's mainly affect? How does it affects its levels? What is it caused by?
excess ACTH production (and increased cortisol) caused by pituitary tumor
47
endogenously derived short acting GC drug
cortisol
48
synthetically derived short acting GC drugs
- prednisolone
- methylprednisolone
49
intermediate acting GC drug
triamcinolone
50
long acting GC drugs
- dexamethasone
- betamethasone
51
difference between potency of synthetic and endogenous GCs
synthetic = better activator of GR
52
difference between specificity of synthetic and endogenous GCs
synthetic bind GR with HIGHER affinity and MR with lower affinity (than endogenous)
53
oral pharmacokinetic considerations for GCs
- effective
- good for systemic treatment
54
topical pharmacokinetic considerations for GCs
- absorbed systemically
- may cause HPA axis inhibition
- inhaled for asthma and COPD
- not appropriate for 11-keto GCs
55
intravenous pharmacokinetic considerations for GCs
- achieve high concentrations rapidly in targeted body fluids
- good for systemic treatment
56
intramuscular pharmacokinetic considerations for GCs
- more prolonged effects
- good for systemic treatments
57
What is the purpose of GC replacement therapy? What are proposed therapies/drugs?
- purpose: replicate circadian rhythm of cortisol secretion
- drugs: chronocort and continuous subcutaneous hydrocortisone infusion (CSHI)
58
What are some non-endocrine uses of GCs?
- anti-inflammatory
- immunosuppressive therapy
- treat neoplastic disease
59
What are GC mechanisms of action as anti-inflammatory agents?
- inhibit transcription of pro-inflammatory gene --> reduce Cox2 --> reduce prostaglandins
- inhibit transcription of pro-inflammatory gene --> reduce interleukins, interferon, tumor necrosis factor
- promote transcription of anti-inflammatory gene --> annexin A1 --> inhibit PLA2 and leukocyte infiltration
60
What are the 2 major drawbacks of GC therapy?
- adverse effects: hypertension, diabetes mellitus, osteoporosis
- GC resistance (inherited and acquired)
61
What are the types of GC antagonists?
- inhibitors of GC synthesis
- GR antagonist
62
list the following for ketoconazole:
- class of GC antagonist
- treat which disease
- mechanism
- side effects
- class: inhibitor of GC synthesis
- disease: Cushing's
- mechanism: inhibitor of 17-alpha-hydroxylase
- side effects: increase in levels of progesterone and aldosterone
63
list the following for metyrapone:
- class of GC antagonist
- treat which disease
- mechanism
- side effects
- class: inhibitor of GC synthesis
- disease: Cushing's
- mechanism: inhibitor of 11-beta-hydroxylase
- side effects: hirsutism and hypertension
64
list the following for mifepristone:
- class of GC antagonist
- mechanism
- treatment for?
- class: GR antagonist
- mechanism: inhibit activation of GR
- treats: ectopic ACTH secretion or adrenal carcinoma
65
What is the goal of selective GR modulators (SGRM)?
- amplify anti-inflammatory effects of GCs
- minimize metabolic effects of GCs
